Endogenous IL-10 is a central mediator of immune homeostasis, necessary to keep in check the strong inflammatory reactions that can accompany the expression of anti-microbial immunity in local tissues. A consequence of the balance struck between host immunity and pathology can be chronic or persistent infection, and the absence of IL-10 has been shown to result in more efficient clearance of a variety of pathogens, including Leishmania major. In Leishmaniasis, aside from the Th2 polarizing conditions that underlie the extreme susceptibility of BALB/c mice to cutaneous strains of Leishmania, chronic forms of cutaneous or visceral disease in humans and in other mouse models are better explained by the presence of ongoing Th1 responses that are compromised in intensity or function by IL-10. As many innate cells and lymphocyte subsets can produce IL-10, the relative contribution of these cells to the anti-inflammatory/immunosuppressive cascade in sites of chronic infection has not been carefully defined. We have addressed the dominant source of IL-10 dependent immune suppression induced by a strain of L. major that produces non-healing dermal lesions in the face of a strong Th1 response in C57BL/6 mice. The infection induced localized recruitment and production of IL-10 from innate cells, as well as from CD4+CD25+Foxp3+ natural Treg and CD4+CD25-Foxp3- inducible Treg. The latter cells appear to be closely linked to the Th1 effector response, in that they also produced high amounts of IFN-gamma. In Rag-/- reconstituted, infected mice, the IL-10-producing Th1 cells were generated in the absence of either natural Treg or IL-10 from innate sources, and most importantly, were found to play a necessary and sufficient role in the suppression of protective immunity in the site. The data are consistent with a regulatory pathway that relies not on a committed lineage of cells or on sub-optimal conditions of immune activation, but on a strong pro-inflammatory environment that drives Th1 cells through a program of development that includes IL-10 secretion as a mechanism of feedback control. [unreadable] [unreadable] Visceral leishmaniasis (VL) is a life threatening disease characterized by uncontrolled parasitization of spleen, liver, and bone marrow. IL-10 has been implicated in the suppression of antigen-specific T cell responses in human VL based on the elevated levels of IL-10 observed in plasma and lesional tissue, and its role in preventing clearance of Leishmania donovani in murine models of VL. The main aim of our clinical studies in India has been to identify the cellular source of IL-10 in human VL, and determine if CD4+CD25+(Foxp3high) regulatory T cells are associated with active disease. We analyzed surface marker and gene expression in PBMC and splenic aspirates from Indian VL patients pre- and 3-4 weeks post-treatment with Amphotericin B. The results did not point to an important role for natural CD4+CD25+(Foxp3high) Treg cells in human VL: they did not accumulate in and were not a major source of IL-10 in the spleen, and their removal did not rescue antigen-specific IFN-gamma responses. By contrast, splenic T cells depleted of CD25+ cells expressed the highest levels of IL-10 mRNA, and were the predominant lymphocyte population in the VL spleen. The data implicate IL-10 producing, adaptive regulatory T cells in immune suppression associated with human VL. [unreadable] [unreadable] CD8+ T cells are generated in response to L. major or T. gondii parasitic infections, indicating that exogenously delivered antigen can be processed for presentation by MHC class I molecules. We have analyzed the potential of transgenic parasites, expressing the model antigen ovalbumin (OVA), to be presented by APC to OVA specific CD8+ T cells. We show that presentation of L. major NT-OVA is TAP-independent in vivo and in vitro, and is inhibited by chloroquine, but not by proteasome inhibitors. In contrast, the presentation of TT. gondii P30-OVA relies on the TAP/proteasome pathway. Presentation of OVA- or recombinant NT-OVA-coated beads also bypassed TAP requirement above a certain antigen threshold. TAP was also dispensable for the presentation of wild-type L. major antigens to primed CD8+ T cells in vitro. Finally, in vivo priming of CD8+ T cells involved in acquired resistance to L. major was not compromised in TAP deficient mice. Thus Leishmania antigens appear to be confined to an intra-phagosomal processing pathway that requires higher concentrations of antigens, suggesting that these parasites may have evolved strategies to impair the efficient ER-based, TAP-dependent cross-presentation pathway to avoid or delay CD8+ T cell priming. A role for the Leishmania surface metalloproteinase, GP63, in remodeling the phagosome and preventing access of secreted antigens to the cytosol is suggested by the finding that DC infected with OVA-secreting GP63 knockout L. major promastigotes presented OVA to CD8+ T cells with much greater efficiency, and utilized a TAP-dependent pathway in vivo.